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The expert faculty addresses clinical syndromes, mechanisms of pathogenesis, molecular therapeutics, and \u2013 importantly \u2013 aspects of career development. The course is available to both pre- and post-graduate trainees, and both clinical- and laboratory-based trainees. We have structured the course so that both groups are together for morning lectures, which emphasize clinical features, molecular pathogenesis, and known potential therapies. In addition, clinical trainees receive training in more specifically clinical activities, and laboratory trainees will take part in wet-lab activities. At the end of each day, the groups join up again for a keynote lecture, and they gather for a banquet with faculty the evening before the course ends. The Clinical Track is primarily directed at clinical fellows (in Neuromuscular Disease; Genetics; Electrophysiology; Physical Medicine & Rehabilitation; etc.), although other specialties and levels of training are welcome, including medical students, residents in Neurology or Pediatrics, and ancillary staff (e.g., nurse practitioners, or physical therapists). The Laboratory Track is directed primarily towards graduate students and Ph.D. post-doctoral fellows who wish to learn new skills, or expand on skill sets relevant to their wor","language":"en"}],"investigator":[{"given":"Leslie","family":"Coonfare","affiliation":[{"id":[{"id":"https:\/\/ror.org\/003rfsp33","id-type":"ROR","asserted-by":"publisher"}],"name":"Nationwide Children's Hospital."}]},{"given":"Leslie","family":"Coonfare","affiliation":[{"id":[{"id":"https:\/\/ror.org\/003rfsp33","id-type":"ROR","asserted-by":"publisher"}],"name":"Nationwide Children's Hospital."}]}],"lead-investigator":[{"ORCID":"http:\/\/orcid.org\/0000-0001-6440-3376","authenticated-orcid":false,"given":"Kevin","family":"Flanigan","affiliation":[{"id":[{"id":"https:\/\/ror.org\/003rfsp33","id-type":"ROR","asserted-by":"publisher"}],"name":"Nationwide Childrens Hospital"}]}],"award-amount":{"amount":11850.0,"currency":null},"award-start":{"date-parts":[[2021,8,30]]},"award-end":{"date-parts":[[2021,12,31]]},"funding":[{"type":"award","funder":{"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}],"name":"Muscular Dystrophy Association"}}]}],"deposited":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T13:10:10Z","timestamp":1685711410000},"score":0.0,"resource":{"primary":{"URL":"https:\/\/proposalcentral.com\/Insights\/Crossref\/PublicAwardRedirect\/pc.gr.147937"}},"issued":{"date-parts":[[2021,8,30]]},"URL":"https:\/\/doi.org\/10.55762\/pc.gr.147937"},{"indexed":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:10:42Z","timestamp":1706055042356},"publisher":"Wellcome","award":"110224","DOI":"10.35802\/110224","type":"grant","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T18:56:13Z","timestamp":1608231373000},"source":"Crossref","prefix":"10.35802","member":"13928","project":[{"project-title":[{"title":"Using genomics to understand the role of cystic fibrosis pathogens in pulmonary exacerbations."}],"project-description":[{"description":"CF is an inherited, life-limiting, multi-system disorder, for which acute deteriorations in lung function termed 'acute pulmonary exacerbations' (APEs) are the single most important cause of morbidity and mortality. Despite this, little is understood about the pathophysiological processes that trigger APEs, although they are thought to be driven by respiratory infections. However, there is no substantive evidence to date that the presence or load of individual species is driving this process. Th is may reflect the complex underlying microbial diversity found in the CF lung at both the inter and intra species level. Therefore, directly sampling of this diversity using high-throughput sequencing will enable major advances in our understanding of APEs. This project involves two approaches which may lead to the discovery of the microbial factors which drive the progression of APE's:(a)Targeted enrichment technology to enable genomic sequencing of multiple CF pathogens concurrently. This w ill enable a greater understanding of the evolutionary dynamics of CF pathogens in the context of APEs. (b)Temporal clonal analysis of Pseudomonas aeruginosa isolates which have been phenotyped for characteristics related to bacterial virulence. By applying a genome wide association analysis we will gain a greater understanding of the relationship between genetic diversity and phenotype.","language":"en"}],"investigator":[{"given":"Josephine","family":"Bryant","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Cambridge","country":"GB"}]}],"award-amount":{"amount":250000.0,"currency":"GBP"},"award-start":{"date-parts":[[2016,3,15]]},"award-end":{"date-parts":[[2022,2,4]]},"funding":[{"type":"grant","scheme":"Pathogen Biology and Disease Transmission","funder":{"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}],"name":"Wellcome Trust"}}]}],"deposited":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T11:09:01Z","timestamp":1706008141000},"score":0.0,"resource":{"primary":{"URL":"https:\/\/europepmc.org\/grantfinder\/grantdetails?query=pi:\"%7BDr%7D%7BBryant%7D%7BJosephine%7D%7BJ%7D\" gid:\"110224\" ga:\"Wellcome Trust\""}},"issued":{"date-parts":[[2016,3,15]]},"URL":"https:\/\/doi.org\/10.35802\/110224"},{"indexed":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:10:42Z","timestamp":1706055042590},"publisher":"Wellcome","award":"208525","DOI":"10.35802\/208525","type":"grant","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T18:55:46Z","timestamp":1608231346000},"source":"Crossref","prefix":"10.35802","member":"13928","project":[{"project-title":[{"title":"Master's Award in Humanities and Social Science"}],"project-description":[{"description":"In my three essays, I will explore case studies of British biotechnology and bioethics since the 1960s. My first essay will investigate the history of organ donation regulation in the UK by focusing on two pieces of legislation: the Human Tissue Act of 1961 and the Human Organ Transplants Act of 1989, which aimed to regulate the procurement of cadaveric and live organ donors, respectively. Next, I will examine the British Biotech controversy of the 1990s. After exaggerating their production of marimastat for cancer treatment, the company lost accreditation and eventually dissolved. I will explore this public controversy using as a key source the episode in BBC2\u2019s series Blood on the Carpet that recorded the politics behind the company\u2019s downfall as a key source. Finally, I will examine the use of Foucauldian ideas in the rise of British bioethics in the 1960s. Focusing specifically on the emergence of what, following Ludwik Fleck, I call the bioethical thought collective, I hope to expand on Daniel Wilson\u2019s work by analyzing how the collective\u2019s philosophical ideals deployed and engaged with Foucault\u2019s concept of biopower. Pursuing these research topics will expand my understanding of current British bioethical debates and American-British policy differences.","language":"en"}],"investigator":[{"ORCID":"http:\/\/orcid.org\/0000-0001-6903-0775","authenticated-orcid":false,"given":"Katie","family":"Cohen","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Cambridge","country":"GB"}]}],"award-amount":{"amount":28440.0,"currency":"GBP"},"award-start":{"date-parts":[[2017,10,1]]},"award-end":{"date-parts":[[2018,7,1]]},"funding":[{"type":"grant","scheme":"Social Science and Bioethics","funder":{"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}],"name":"Wellcome Trust"}}]}],"deposited":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T11:10:04Z","timestamp":1706008204000},"score":0.0,"resource":{"primary":{"URL":"https:\/\/europepmc.org\/grantfinder\/grantdetails?query=pi:\"%7BMiss%7D%7BCohen%7D%7BKatie%7D%7BK%7D\" gid:\"208525\" ga:\"Wellcome Trust\""}},"issued":{"date-parts":[[2017,10,1]]},"URL":"https:\/\/doi.org\/10.35802\/208525"},{"indexed":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:10:44Z","timestamp":1706055044478},"publisher":"Wellcome","award":"200873","DOI":"10.35802\/200873","type":"grant","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T18:55:46Z","timestamp":1608231346000},"source":"Crossref","prefix":"10.35802","member":"13928","project":[{"project-title":[{"title":"The molecular machinery of RNA metabolism and riboregulation in bacteria"}],"project-description":[{"description":"In response to stress conditions and environmental changes, bacteria generate scores of small RNAs that play key roles in reshaping the dynamic landscape of gene expression. This process involves chaperone proteins that facilitate the actions of such regulatory RNAs and enzymes that affect transcript lifetimes. We aim to understand the molecular basis of these processes. Trapped intermediates of the degradative machinery with bound regulatory RNAs and targeted substrates will be structurally characterised to visualize how transcripts are captured and channelled to active sites, where they meet a fate of rapid degradation or processing into matured forms. We will identify RNA targets of chaperones and the degradative machinery and explore whether the patterns change with physiological state or during the cell cycle, and why. We want to understand why the degradative machinery has a sub-cellular localization and the origins of its dynamic and cooperative interactions with substrates and the translational machinery. Our studies will help to explain how the use of RNA enables speed and accuracy to be attained in genetic regulation and enriches the capacity of even the simplest organisms to exhibit complex behaviour in homeostasis, development and pathogenesis. This knowledge could be exploited to treat threatening bacterial infections.","language":"en"},{"description":"<p>A critical step in the production of proteins is the translation of nucleotide sequence in messenger RNA molecules into amino acid sequences in proteins. It is well known that protein molecules in turn bind RNA and regulate translation. Other molecules called small regulatory RNAs are often involved in regulating this process: these bind to the messenger RNAs to modulate protein production. Bacteria and other microorganisms use small regulatory RNAs to respond to stress conditions and environmental changes. The ability to rapidly adapt to these changes enables bacteria to withstand harmful conditions, and to use efficiently available resources available; it also helps orchestrate complex programmes of gene expression involved in infection of hosts. For many small RNAs, interactions with messenger RNAs are facilitated by protein chaperones. In some cases the chaperone protects the small RNAs or helps to interact with target RNAs, and then recruits enzymes that eventually degrade the complex formed by the RNA molecules. The project will study the key players involved in the processing and turnover of RNA and the use of RNA to control gene expression in model bacteria. Our experiments will explore how the components cooperate to regulate gene expression in a controlled and effective manner.<\/p>","language":"en"}],"investigator":[{"ORCID":"http:\/\/orcid.org\/0000-0003-1144-9877","authenticated-orcid":false,"given":"Bonaventura","family":"LUISI","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Cambridge","country":"GB"}]}],"award-amount":{"amount":1630519.0,"currency":"GBP"},"award-start":{"date-parts":[[2016,8,1]]},"award-end":{"date-parts":[[2021,11,28]]},"funding":[{"type":"grant","scheme":"Molecular Basis of Cell Function","funder":{"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}],"name":"Wellcome Trust"}}]}],"deposited":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T11:08:21Z","timestamp":1706008101000},"score":0.0,"resource":{"primary":{"URL":"https:\/\/europepmc.org\/grantfinder\/grantdetails?query=pi:\"%7BProf%7D%7BLUISI%7D%7BBonaventura%7D%7BB%7D\" gid:\"200873\" ga:\"Wellcome Trust\""}},"issued":{"date-parts":[[2016,8,1]]},"URL":"https:\/\/doi.org\/10.35802\/200873"},{"indexed":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:10:45Z","timestamp":1706055045248},"publisher":"Wellcome","award":"203828","DOI":"10.35802\/203828","type":"grant","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T18:59:26Z","timestamp":1608231566000},"source":"Crossref","prefix":"10.35802","member":"13928","project":[{"project-title":[{"title":"University of Cambridge - Mathematical Genomics and Medicine"}],"project-description":[{"description":"Imperial College London - Theoretical Systems Biology and Bioinformatics","language":"en"}],"investigator":[{"ORCID":"http:\/\/orcid.org\/0000-0003-3597-6591","authenticated-orcid":false,"given":"Daniel","family":"Kunz","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Cambridge","country":"GB"}]}],"award-amount":{"amount":133023.0,"currency":"GBP"},"award-start":{"date-parts":[[2016,10,1]]},"award-end":{"date-parts":[[2020,10,1]]},"funding":[{"type":"grant","scheme":"Genetics, Genomics and Population Research","funder":{"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}],"name":"Wellcome Trust"}}]}],"deposited":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T11:08:08Z","timestamp":1706008088000},"score":0.0,"resource":{"primary":{"URL":"https:\/\/europepmc.org\/grantfinder\/grantdetails?query=pi:\"%7BMr%7D%7BKunz%7D%7BDaniel%7D%7BD%7D\" gid:\"203828\" ga:\"Wellcome Trust\""}},"issued":{"date-parts":[[2016,10,1]]},"URL":"https:\/\/doi.org\/10.35802\/203828"},{"indexed":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:10:46Z","timestamp":1706055046333},"publisher":"Wellcome","award":"070266","DOI":"10.35802\/070266","type":"grant","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T18:59:26Z","timestamp":1608231566000},"source":"Crossref","prefix":"10.35802","member":"13928","project":[{"project-title":[{"title":"Action of Salmonella effector proteins during mammalian cell entry."}],"investigator":[{"ORCID":"http:\/\/orcid.org\/0000-0002-1353-1092","authenticated-orcid":false,"given":"Vassilis","family":"Koronakis","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Cambridge","country":"GB"}]}],"award-start":{"date-parts":[[2003,8,1]]},"award-end":{"date-parts":[[2009,1,31]]},"funding":[{"type":"grant","scheme":"Immune System in Health and Disease","funder":{"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}],"name":"Wellcome Trust"}}]}],"deposited":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T10:46:02Z","timestamp":1706006762000},"score":0.0,"resource":{"primary":{"URL":"https:\/\/europepmc.org\/grantfinder\/grantdetails?query=pi:\"%7BProfessor%7D%7BKoronakis%7D%7BVassilis%7D%7BV%7D\" gid:\"070266\" ga:\"Wellcome Trust\""}},"issued":{"date-parts":[[2003,8,1]]},"URL":"https:\/\/doi.org\/10.35802\/070266"},{"indexed":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:10:44Z","timestamp":1706055044797},"publisher":"Wellcome","award":"206617","DOI":"10.35802\/206617","type":"grant","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T18:55:46Z","timestamp":1608231346000},"source":"Crossref","prefix":"10.35802","member":"13928","project":[{"project-title":[{"title":"The role of Eros in Innate and Adaptive Immunity"}],"project-description":[{"description":"I will investigate the role of a novel protein, Eros, in immunity. I discovered the fundamental importance of this protein by demonstrating that Eros-deficient mice die from Salmonella infection because their phagocytes cannot make reactive oxygen species. This is because Eros is essential for expression of vital components of the phagocyte NADPH oxidase. My work represents the only paper on this protein. I have found that Eros-deficiency has effects that go far beyond the generation of reactive oxygen species. In particular: \u2022 Eros regulates the expression of other key macrophage proteins including P2X7, a key activator of the NLRP3 inflammasome \u2022 Eros regulates the expression of numerous cytokines from CD4+ T cells. Eros -\/- T cells make 10-fold more IL-4 than control cells In mouse and human systems, I will investigate the molecular mechanisms by which Eros: \u2022 controls the abundance of a subset of proteins working on the hypothesis that it is a novel component of the protein quality control pathway using structural, biochemical and cell biological techniques. \u2022 controls T cell cytokine secretion. I will spend time working with John O'Shea, a world leader in this field.","language":"en"}],"investigator":[{"ORCID":"http:\/\/orcid.org\/0000-0002-9738-2329","authenticated-orcid":false,"given":"David","family":"Thomas","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Cambridge","country":"GB"}]}],"award-amount":{"amount":1319075.0,"currency":"GBP"},"award-start":{"date-parts":[[2017,10,1]]},"award-end":{"date-parts":[[2022,10,1]]},"funding":[{"type":"grant","scheme":"Immune System in Health and Disease","funder":{"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}],"name":"Wellcome Trust"}}]}],"deposited":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T11:10:24Z","timestamp":1706008224000},"score":0.0,"resource":{"primary":{"URL":"https:\/\/europepmc.org\/grantfinder\/grantdetails?query=pi:\"%7BDr%7D%7BThomas%7D%7BDavid%7D%7BD%7D\" gid:\"206617\" ga:\"Wellcome Trust\""}},"issued":{"date-parts":[[2017,10,1]]},"URL":"https:\/\/doi.org\/10.35802\/206617"},{"indexed":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:10:47Z","timestamp":1706055047370},"publisher":"Wellcome","award":"206853","DOI":"10.35802\/206853","type":"grant","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T18:55:46Z","timestamp":1608231346000},"source":"Crossref","prefix":"10.35802","member":"13928","project":[{"project-title":[{"title":"Behaviour Change by Design: Generating and Implementing Evidence to Improve Health for All"}],"project-description":[{"description":"Reducing food, alcohol and tobacco consumption would dramatically reduce non-communicable disease and, since these behaviours cluster by deprivation, would also reduce health inequalities. However, progress in achieving such behaviour change is slow. Traditional approaches to behaviour change involve providing information with, at best, modest population-level effects and sometimes increased inequalities. Conversely, Choice Architecture interventions (\u201cNudges\u201d) have potentially larger, more equitable effects, involving re-designing environments e.g. reducing plate size to reduce food consumption. However, evidence of effectiveness in real-world settings and understanding of mechanisms are limited. We will bridge this knowledge gap through a novel collaboration between behavioural and cognitive sciences. In the most ambitious co-ordinated set of studies to date, we propose field studies to estimate effect sizes of promising Choice Architecture interventions to reduce food, alcohol and tobacco consumption. Enabled by unprecedented collaborations, these will be conducted in supermarkets, bars and cafeterias and interventions optimised through laboratory studies determining mechanisms. We will run international workshops, public engagement activities and a Behaviour Change Summit to facilitate implementing the evidence generated, overseen by an Implementation Advisory Panel. This will enable us to realise our vision of accelerating progress in changing behaviour by re-designing environments to improve health for all.","language":"en"},{"description":"If people ate less, drank less alcohol and didn't smoke, diseases like diabetes and many cancers would be far less common. Because these unhealthy behaviours are more common amongst the poorest, they contribute to the gaps in health and life expectancy between the richest and the poorest. Progress in changing these behaviours is slow. Traditional approaches to changing behaviour are often based on giving information. They are generally ineffective, particularly amongst the poorest. Choice Architecture interventions (\"Nudging\") are potentially more effective and equitable, involving re-designing environments, e.g. reducing plate size to reduce how much people eat. But evidence is lacking on how effective such interventions are in real-world settings. We propose a novel collaboration between behavioural and cognitive sciences addressing this knowledge gap. In a series of studies we will evaluate the most promising interventions to reduce consumption of food, alcohol and tobacco, conducted in supermarkets, bars and cafeterias, using laboratory studies to understand and optimize the interventions. We will facilitate implementing the evidence generated through various activities overseen by an Implementation Advisory Panel, to fully realise our vision of accelerating progress in changing behaviour by re-designing environments to improve health for all.","language":"en"}],"investigator":[{"ORCID":"http:\/\/orcid.org\/0000-0003-3025-1129","authenticated-orcid":false,"given":"Theresa","family":"Marteau","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Cambridge","country":"GB"}]}],"award-amount":{"amount":3123724.0,"currency":"GBP"},"award-start":{"date-parts":[[2018,1,2]]},"award-end":{"date-parts":[[2022,1,2]]},"funding":[{"type":"grant","scheme":"Population and Public Health","funder":{"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}],"name":"Wellcome Trust"}}]}],"deposited":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T11:10:54Z","timestamp":1706008254000},"score":0.0,"resource":{"primary":{"URL":"https:\/\/europepmc.org\/grantfinder\/grantdetails?query=pi:\"%7BProf Dame%7D%7BMarteau%7D%7BTheresa%7D%7BTM%7D\" gid:\"206853\" ga:\"Wellcome Trust\""}},"issued":{"date-parts":[[2018,1,2]]},"URL":"https:\/\/doi.org\/10.35802\/206853"},{"indexed":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:10:49Z","timestamp":1706055049465},"publisher":"Wellcome","award":"082961","DOI":"10.35802\/082961","type":"grant","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T18:59:26Z","timestamp":1608231566000},"source":"Crossref","prefix":"10.35802","member":"13928","project":[{"project-title":[{"title":"Protein crystallography: development of new methods, and application to the study of pathogenesis."}],"project-description":[{"description":"The proposed research is in the area of protein crystallography, involving both the development of new methods, and applications to the study of proteins relevant to disease. Crystallographic methods in our new computer program Phaser are based on the principle of maximum likelihood, which requires an understanding of the statistical relationships among experimental observations. We will build on success in the area of molecular replacement to solve structures with less prior knowledge, usin g either smaller fragments or ab initio models. We will complete the implementation of experimental phasing by multiple-wavelength isomorphous replacement and two-wavelength anomalous diffraction, and we will explore other applications, for instance to phasing in the presence of radiation damage. In our structural research, we will complete our study of the enzymatic mechanism of pertussis toxin by determining structures representing the Michaelis complex. We will study the mechanism by whi ch the hormone-binding globulins carry out a targeted release of bound hormone, and will attempt to exploit that understanding to design variants that release selected drugs at selected target sites. Finally, we will begin a new study on enzymes mutated in lysosomal storage diseases, with the eventual goal of contributing to improvements in enzyme replacement therapy.","language":"en"}],"investigator":[{"ORCID":"http:\/\/orcid.org\/0000-0001-8273-0047","authenticated-orcid":false,"given":"Randy","family":"Read","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Cambridge","country":"GB"}]}],"award-amount":{"amount":2485913.0,"currency":"GBP"},"award-start":{"date-parts":[[2008,6,1]]},"award-end":{"date-parts":[[2018,6,4]]},"funding":[{"type":"grant","scheme":"Cellular and Molecular Neuroscience","funder":{"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}],"name":"Wellcome Trust"}}]}],"deposited":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T10:53:00Z","timestamp":1706007180000},"score":0.0,"resource":{"primary":{"URL":"https:\/\/europepmc.org\/grantfinder\/grantdetails?query=pi:\"%7BProfessor%7D%7BRead%7D%7BRandy%7D%7BRJ%7D\" gid:\"082961\" ga:\"Wellcome Trust\""}},"issued":{"date-parts":[[2008,6,1]]},"URL":"https:\/\/doi.org\/10.35802\/082961"},{"indexed":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:10:49Z","timestamp":1706055049548},"publisher":"Wellcome","award":"101241","DOI":"10.35802\/101241","type":"grant","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T18:56:13Z","timestamp":1608231373000},"source":"Crossref","prefix":"10.35802","member":"13928","project":[{"project-title":[{"title":"Characterization of novel E3 ubiquitin ligases that are enriched in LGR5-positive intestinal stem cells and niche."}],"project-description":[{"description":"In the intestine, LGR5-positive (LGR5+) crypt base columnar cells comprise a well-defined adult stem cell population. FACS isolation of LGR5-positive intestinal stem cells have facilitated the expression profiling of LGR5+ stem cells, which established stem cell-specific genes of the adult intestine. Amongst are two homologous E3 ubiquitin ligases, RNF43 and ZNRF3, the inactivation of which resulted in unrestricted expansion of intestinal stem cells and formation of adenomas due to hyper-activat ion of Wnt signalling. This has started uncovering the importance of E3 ligases in regulating intestinal stem cells. Besides RNF43 and ZNRF3, additional uncharacterized E3 ubiquitin ligases are enriched in intestinal stem cells. By using cell-surface marker CD24 to sort and profile Paneth cells, novel additional E3 ubiquitin ligases were also detected in these niche cells. These novel E3 ubiquitin ligases are the focus of this research plan, since it is anticipated that they play an important ro le in stem cells, niche cells and their interaction. 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Both KIR and HLA-C are polymorphic and genetic studies show that NK cells respond inadequately in certain maternal KIR\/HLA-C combinations. KIR\/HLA-C interactions are predicted to have particular biological importance during placentation because of high expression levels of KIR on uNK cells and HLA-C on trophoblast. We will study functio nal responses of primary uterine NK cells in women with known KIR genotypes using in vitro assays that mimic different maternal KIR\/fetal HLA-C combinations. A particular focus will be on KIR2DS1, the activating KIR for HLA-C2 group alleles, because women with a C2+ fetus are at particular risk of pre-eclampsia if they lack the KIR2DS1 gene. Using functional read-outs - including CD107 assays, cytokine production and microarrays, we will analyse how KIR2DS1+ or KIR2DS1- uNK subsets respond to targets expressing C1 or C2 and to primary trophoblast cells whose HLA-C status is known. 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Successful pregnancy and fetal growth depends on trophoblast infiltration into the uterus and this is most severely deficient in women who have pre-eclampsia and the baby also has FGR. We have access to 100,000 Norwegian samples and can select adequate numbers of these severely abnormal pregnancies to compare with normal controls. We will determine individual KIR gene frequencies and type HLA-C alleles on mother and baby. For the first time we will address how the mother s HLA-C status affects the response of uNK to the fetal trophoblast. We will also focus on one particular KIR, KIR2DL1 and address how polymorphism of this gene encoding the receptor for HLA-C2 alleles influences pregnancy outcome and uNK function. Finally, we aim to translate the genetic studies into functional outcomes usi ng primary uterine NK cells and normal trophoblast. These studies will reveal how the complex system of interacting maternal KIR receptors and fetal HLA-C ligands are critical determinants of clinical outcomes during pregnancy.","language":"en"}],"investigator":[{"ORCID":"http:\/\/orcid.org\/0000-0002-8388-9073","authenticated-orcid":false,"given":"Ashley","family":"Moffett","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Cambridge","country":"GB"}]}],"award-amount":{"amount":442655.0,"currency":"GBP"},"award-start":{"date-parts":[[2008,12,1]]},"award-end":{"date-parts":[[2011,11,30]]},"funding":[{"type":"grant","scheme":"Immune System in Health and Disease","funder":{"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}],"name":"Wellcome Trust"}}]}],"deposited":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T10:54:36Z","timestamp":1706007276000},"score":0.0,"resource":{"primary":{"URL":"https:\/\/europepmc.org\/grantfinder\/grantdetails?query=pi:\"%7B%7D%7BMoffett%7D%7BAshley%7D%7BA%7D\" gid:\"085992\" ga:\"Wellcome Trust\""}},"issued":{"date-parts":[[2008,12,1]]},"URL":"https:\/\/doi.org\/10.35802\/085992"},{"indexed":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:10:53Z","timestamp":1706055053499},"publisher":"Wellcome","award":"093735","DOI":"10.35802\/093735","type":"grant","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T18:56:13Z","timestamp":1608231373000},"source":"Crossref","prefix":"10.35802","member":"13928","project":[{"project-title":[{"title":"Genome-wide analysis of the interactions that mediate communication between central carbon metabolism and the cellular regulome"}],"project-description":[{"description":"Cells exposed to oxidants re-route their main carbon flow from glycolysis to the pentose phosphate pathway (PPP), by two different mechanisms. One bases on a biochemical block and operates purely on a metabolic level, the other on transcriptional regulation. We found that the two processes compartmentalize over time: After contact with the stressor, the cell induces the metabolic transition in seconds-timescale but it takes minutes until transcripts raise. Remarkably, metabolic changes seem cau sally implicated in regulating this process: induction of the transition activates transcripts of the antioxidant-system. It is the aim of this proposal to identify and analyze regulatory mechanisms which surround the involved metabolic pathways on a genome-scale level. For this, we will develop multiple reaction monitoring (MRM) assays that allow fast quantification of metabolic intermediates, and screen an entire yeast knock-out library composed of 5,200 systematically generated yeast mutants to identify all gene deletions which cause specific changes in the concentration of their intermediates. In a second step, by using a targeted proteomics strategy, these mutants will be screened to identify alterations in the abundance of implicated enzymes. The identified genetic\/metabolome interactions are studied for their general importance on metabolism, and analyzed in respect of yeast aging phenotypes.","language":"en"}],"investigator":[{"ORCID":"http:\/\/orcid.org\/0000-0001-9535-7413","authenticated-orcid":false,"given":"Markus","family":"Ralser","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Cambridge","country":"GB"}]}],"award-amount":{"amount":883906.0,"currency":"GBP"},"award-start":{"date-parts":[[2011,5,1]]},"award-end":{"date-parts":[[2017,4,30]]},"funding":[{"type":"grant","scheme":"Genetics, Genomics and Population Research","funder":{"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}],"name":"Wellcome 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